Mode of Action of Kanglemycin A, an Ansamycin Natural Product that Is Active against Rifampicin-Resistant Mycobacterium tuberculosis

Hamed Mosaei, Vadim Molodtsov, Bernhard Kepplinger, John Harbottle, Christopher William Moon, Rose Elizabeth Jeeves, Lucia Ceccaroni, Yeonoh Shin, Stephanie Morton-Laing, Emma Claire Louise Marrs, Corinne Wills, William Clegg, Yulia Yuzenkova, John David Perry, Joanna Bacon, Jeff Errington, Nicholas Edward Ellis Allenby, Michael John Hall, Katsuhiko S. Murakami, Nikolay Zenkin

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Antibiotic-resistant bacterial pathogens pose an urgent healthcare threat, prompting a demand for new medicines. We report the mode of action of the natural ansamycin antibiotic kanglemycin A (KglA). KglA binds bacterial RNA polymerase at the rifampicin-binding pocket but maintains potency against RNA polymerases containing rifampicin-resistant mutations. KglA has antibiotic activity against rifampicin-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis (MDR-M. tuberculosis). The X-ray crystal structures of KglA with the Escherichia coli RNA polymerase holoenzyme and Thermus thermophilus RNA polymerase-promoter complex reveal an altered—compared with rifampicin—conformation of KglA within the rifampicin-binding pocket. Unique deoxysugar and succinate ansa bridge substituents make additional contacts with a separate, hydrophobic pocket of RNA polymerase and preclude the formation of initial dinucleotides, respectively. Previous ansa-chain modifications in the rifamycin series have proven unsuccessful. Thus, KglA represents a key starting point for the development of a new class of ansa-chain derivatized ansamycins to tackle rifampicin resistance. Resistance to rifamycins, inhibitors of bacterial RNA polymerase used for treatment of tuberculosis, is increasing. Mosaei et al. report an analog of the rifamycins, kanglemycin A, that inhibits rifampicin-resistant RNA polymerases and is effective against multidrug-resistant M. tuberculosis, and they describe its mechanism of action.

Original languageEnglish (US)
Pages (from-to)263-274.e5
JournalMolecular cell
Volume72
Issue number2
DOIs
StatePublished - Oct 18 2018

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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